Conjugated linoleic acids (CLAs) have received considerable attention recently because of reports that they may have chemoprotective properties.
CLAs (notably 9,11- and 10,12-octadecadienoic acids or, more simply, 9,11-18:2 or 10,12-18:2) are isomers of linoleic acid (9,12-linoleic acid). The term "CLA" is used in a generalized sense to refer to certain positional and geometrical isomers of linoleic acid, these isomers being characterized by the presence of a set of conjugated double bonds which differentiate the CLAs from the precursor linoleic acid, the latter being characterized by a non-conjugated pair of double bonds at the C-9 and C-12 positions. The CLAs are primarily the 9,11- and/or 10,12-isomers, each of which has possible cis and trans configurations at the double bonds.
CLAs have been found predominantly in meat and dairy products (1-2). CLA content is highest in ruminant meats. For example, lamb contains 6 mg of CLAs per gram of fat with smaller amounts being found in poultry and eggs. Dairy products also contain considerable amounts of CLAs. For example, homogenized milk has about 5.5 mg/g of fat.
In the past few years, CLAs have generated considerable interest in cancer and cardiovascular research. A variety of reports have appeared indicating that CLAs may be effective in inhibiting the initiation and/or post-initiation phases of carcinogenesis in several experimental animal models (3-5). CLAs have also been reported as decreasing the incidence of chemically induced skin and forestomach cancers in mice and mammary tumors in rats. Other findings indicate that CLAs have reduced in vitro cell growth when added to malignant melanoma cells, colorectal cancer cells and human breast cancer cells.
As far as the effects of CLAs on cardiovascular disease are concerned, Kritchevsky and co-workers have reported the suppression of atherosclerosis in rabbits (6). Thus, when rabbits were fed an atherogenic diet containing CLA, a decrease in total plasma- and LDL cholesterol levels was observed. In another study, Nicolosi found that addition of CLA to the diet of hamsters reduced LDL-cholesterol levels and aortic atherosclerosis (7).
Although there are probably a variety of mechanisms by which CLAs inhibit carcinogenesis and reduce cholesterol levels, none of these mechanisms has yet been conclusively identified. Previous reports have suggested that certain prostanoid inhibitors may be effective in preventing the initiation of chemical carcinogenesis (8) and, in view of this, one might speculate that CLAs function in a similar manner, possibly by preventing prostanoid formation. However, until the present invention, the use of CLAs to control prostanoid formation has not been disclosed.
Prostanoids are members of the eicosanoid family of metabolites formed from arachidonic acid (see FIG. 1). Eicosanoids are produced by most mammalian cell types and are potent cellular regulators that function as local mediators since they act at or near the location at which they are synthesized (9). For example, the eicosanoids are known to mediate induction of blood clotting and a variety of inflammatory responses.
There are two main pathways of arachidonic acid metabolism in the body. One is the so-called "cyclic" or cyclooxygenase-catalyzed pathway and a second one, the "linear" or lipoxygenase-catalyzed route [(9), FIG. 1]. The cyclic pathway generates prostanoids including prostaglandins and thromboxane, for example, thromboxane A.sub.2 (TXA.sub.2) which is a very potent inducer of platelet aggregation. The lipoxygenase-mediated pathway, on the other hand, produces hydroperoxy derivatives of arachidonic acid. A variety of cells can produce the 5-hydroperoxy metabolite which is the precursor of the leukotriene group of substances that are potent contractors of vascular smooth muscle and constrictors of lung bronchi.
Several prior studies have shown that different fatty acids can act as competitors of both the cyclooxygenase and lipoxygenase enzymes (10). However, it appears that there has been no study regarding the activity of CLAs with respect to these enzymes.